IL-17-driven mechanisms for tumor progression and resistance to therapies

IL-17 驱动的肿瘤进展和治疗耐药机制

• 批准号: 10493940
• 负责人: Xiaoxia Li
• 金额: $ 52.03万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493940
• 关键词: Animal Model; Automobile Driving; Award; Binding; CD8-Positive T-Lymphocytes; Cells; Chemoresistance; Chronic; Cisplatin; Collagen; Cutaneous; Data; Deposition; Development; Dissection; Environment; Epidermal Growth Factor Receptor; Exclusion; Fibroblasts; Genes; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukins; Knowledge; Link; MAPK7 gene; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; Myeloid-derived suppressor cells; Pathogenicity; Population; Process; Prognosis; Proteins; RNA Binding; Refractory; Reporting; Resistance; Role; Shapes; Signal Transduction; Solid Neoplasm; Squamous cell carcinoma; Standardization; Statistical Data Interpretation; Stromal Cells; Testing; Therapeutic; Transcript; Transforming Growth Factor beta; Translations; Work; antagonist; anti-PD-1; anti-PD1 therapy; base; cancer cell; cancer cell differentiation; cancer therapy; chemotherapy; cytokine; design; improved; in vivo; insight; neoplastic cell; novel therapeutic intervention; pre-clinical assessment; prevent; programs; response; single cell analysis; stem; stem cells; stemness; therapeutic target; therapy resistant; tool; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenesis; wound healing

Project Summary While the relationship between chronic inflammation and cancer is well recognized, knowledge of the cellular and molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17) levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of this application is to investigate the mechanisms of IL-17-mediated cancer progression, focusing on tumor responses to anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumor microenvironment to synergistically promote cancer progression. Firstly, work supported by this award identified a non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our new preliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highly responsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5 axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependent induction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistance to chemotherapy, which were also enriched by anti-PD1 treatment. Secondly, we found that canonical IL-17 signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressive environment. In tumor cells, IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoral cancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblasts, IL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletion of IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations, we hypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancer progression and resistance to therapies. To test this hypothesis, we will (1) Investigate how IL-17R-EGFR axis in Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by which IL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project will be critically informed by and also provide necessary information to the other Projects in the Program at multiple levels. Project 1 and Project 2 will investigate the antagonistic interplay between IFNβ and TGFβ in cancer cell differentiation. Informed by those studies, we will determine whether STING-induced IFNβ can be used to eradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the Animal Model, Immunotyping and Analytics Core B to standardize our in vivo analyses, including preclinical assessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statistical analyses will be performed by Program Biostatistician Dr. Bo Hu and Program Bioinformatician Dr. Fulai Jin (Core B).

项目摘要 虽然慢性炎症和癌症之间的关系是公认的，但对细胞炎症的认识还不够。 连接这些过程的分子机制也在不断进化。肿瘤内白细胞介素17 A（IL-17） 水平与人类多种实体瘤的不良预后相关。总的目标是 应用是研究IL-17介导的癌症进展的机制，重点是肿瘤反应 到抗癌疗法。我们最近的初步数据显示，IL-17与癌细胞和肿瘤细胞结合， 微环境协同促进癌症进展。首先，该奖项支持的工作确定了 一种非经典的IL-17诱导的EGFR介导的ERK 5信号级联反应，对肿瘤发生至关重要。我们的新 初步研究显示，鳞状细胞癌中的Lrig 1+干细胞样肿瘤细胞群高度表达， 对IL-17有应答的EGFR-ERK 5活化。转录组学分析揭示了IL-17-ERK 5 人和小鼠Lrig 1+干细胞样肿瘤细胞中NRF 2介导的抗氧化和Wnt 5a依赖性 干性诱导。谱系追踪显示，IL-17使这些Lrig 1+干细胞样肿瘤细胞耐药 化疗，这也是丰富的抗PD 1治疗。其次，我们发现典型的IL-17 信号传导在肿瘤细胞和基质细胞中起作用， 环境在肿瘤细胞中，IL-17与其他炎性细胞因子协同作用， 通过诱导特异性效应分子而促进炎症的癌症。在癌症相关的成纤维细胞中， IL-17信号传导有助于建立免疫排斥区，以防止CD 8 + T细胞的浸润。删除 CAF中IL-17 R的表达使这些肿瘤对免疫治疗敏感。根据这些观察，我们 假设癌细胞和CAF中典型和非典型IL-17信号传导协同驱动癌症 进展和对治疗的抗性。为了验证这一假设，我们将（1）研究IL-17 R-EGFR轴 在Lrig 1+干细胞样肿瘤细胞中， IL-17塑造促肿瘤免疫排斥肿瘤微环境。项目合作：本项目将 在多个项目中，向其他项目提供重要信息，并向其他项目提供必要的信息。 程度.项目1和项目2将研究IFNβ和TGFβ在癌细胞中的拮抗作用 分化通过这些研究，我们将确定STING诱导的IFNβ是否可以用于 根除Lrig 1+细胞以改善对抗癌疗法的反应。我们会利用动物 模型、免疫分型和分析核心B，用于标准化我们的体内分析，包括临床前分析 癌症治疗的评估和肿瘤微环境（TME）的表征。统计 将由项目生物统计学家胡波博士和项目生物信息学家金福来博士进行分析 (Core B）。